This proposal builds on previous research that developed the dog as a model for the genetic analysis of complex traits. A working relationship with owners and breeders of Portuguese Water Dogs (PW dogs) has led to a database of more than 1000 animals that have been genotyped with molecular markers and more than half of these have been phenotyped for skeletal morphology. Results from that genetic analysis were instrumental in securing the necessary priority leading to the sequencing of the canine genome. Most recent research on this project demonstrated that conclusions from this database could be validated using other breeds of dogs leading to haplotype sequences of reduced length, focused on specific genes. In the current proposal, genetic analysis focuses on disease related phenotypes: Genetic loci will be identified that regulate the serum chemistry of healthy dogs (bio-markers related to disease states) and that regulate the state of health of PW dogs at time of death determined by autopsy. The latter analysis should provide genetic data on degenerative diseases that occur as part of the aging process. Autopsy data also provides analysis of the genetic regulation of organs, skulls, and soft tissues avoiding invasive procedures performed on living animals. Genetic analysis will utilize two approaches developed in the last three years: Analysis of segregating haplotypes within a single breed (PW dog) in which heritable variation has been documented;and analysis of fixed haplotypes that differ between breeds (genetic isolates) that exhibit different breed-wide fixed phenotypes. In PW dog sera various aspects of serum chemistry are heritable and segregating loci have been demonstrated for several biomarkers. Differences between breeds (fixed phenotypes) also have been demonstrated for mean values of serum biomarkers. Values of serum biomarkers as well as frequency of diseases are available from extensive public databases. Autopsy data are obtained on PW dogs sent to the Utah performance site. 200 such autopsies have been carried out demonstrating the viability of this approach. Approximately 50 organ and tissue phenotypes are obtained from gross autopsy and a similar number from histopathology of tissue sections. Genotyping is carried out using the Affymetrix SNP chip. The analysis of this increasing database is a collaborative effort between the Utah site and the NIH laboratory of Dr. Elaine Ostrander. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Dogs share more than 200 genetic diseases in common with man, which are diagnosed with similar serum biomarkers and present most of the same histopathologies as in humans. This research will identify genetic loci that regulate variation in serum biomarkers of the dog and that control disease pathology. Results will be directly applicable to the diagnosis of human genetic diseases and the predisposition to genetic disease. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page